Muscarinic acetylcholine receptor subtype 4 antagonists in the treatment of anemia
View Patent ↗This disclosure generally relates to treating anemias. More specifically, the disclosure relates to use of muscarinic acetylcholine receptor subtype 4 antagonists, such as small molecule compounds, to promote self-renewal of burst forming unit erythroid (BFU-E) cells and treat anemias.
1 . A compound of the formula:
wherein:
R 1 is H or CH 3 ;
R 2 is a hydrocarbon group having 1-3 carbon atoms;
R 3 , R 4 , and R 5 are independently selected from hydrogen atom, halogen atoms, CH 3 , CF 3 , OH, OCH 3 , SH, SCH 3 , and the following structure (1-1):
provided that one or two of R 3 , R 4 , and R 5 is the structure of Formula (1-1);
R 6 is CH 3 ;
R 7 , R 8 , and R 9 are independently selected from hydrogen atom, halogen atoms, CH 3 , CF 3 , OH, OCH 3 , SH, and SCH 3 ;
and wherein the compound of Formula (1) includes pharmaceutically acceptable salts, solvates, enantiomers, and polymorphs of said compound of Formula (1).
2 . The compound of claim 1 , wherein the compound has the following formula:
3 . The compound of claim 1 , wherein the compound has the following formula:
4 . The compound according to claim 1 , wherein R 1 is a hydrogen atom.
5 . The compound according to claim 1 , wherein R 1 is methyl.
6 . The compound according to claim 1 , wherein R 2 is ethyl.
7 . The compound according to claim 1 , wherein R 1 is hydrogen atom and R 2 is ethyl.
8 . The compound according to claim 1 , wherein R 1 is methyl and R 2 is ethyl.
9 . A compound of the formula:
wherein:
R 1 is H or CH 3 ;
R 2 is a hydrocarbon group having 1-3 carbon atoms;
R 3 , R 4 , and R 5 are independently selected from hydrogen atom, halogen atoms, CH 3 , CF 3 , OH, OCH 3 , SH, SCH 3 , and the following structure (1-2):
provided that one or two of R 3 , R 4 , and R 5 is the structure of Formula (1-2);
R 6 is H or CH 3 ;
R 7 , R 8 , and R 9 are independently selected from hydrogen atom, halogen atoms, CH 3 , CF 3 , OH, OCH 3 , SH, and SCH 3 ;
X − is an anion to counterbalance the positively charged portion of the compound; and
wherein the compound of Formula (1c) includes pharmaceutically acceptable salts, solvates, enantiomers, and polymorphs of said compound of Formula (1c).
10 . The compound of claim 9 , wherein the compound has the following formula:
11 . The compound of claim 9 , wherein the compound has the following formula:
12 . The compound according to claim 9 , wherein R 1 is a hydrogen atom.
13 . The compound according to claim 9 , wherein R 1 is methyl.
14 . The compound according to claim 9 , wherein R 2 is ethyl.
15 . The compound according to claim 9 , wherein R 1 is hydrogen atom and R 2 is ethyl.
16 . The compound according to claim 9 , wherein R 1 is methyl and R 2 is ethyl.
17 . A compound of the formula:
R 1 is H or CH 3 ;
R 2 is a hydrocarbon group having 1-3 carbon atoms;
R 4 , R 5 , R 7 , R 8 , and R 9 are independently selected from hydrogen atom, halogen atoms, CH 3 , CF 3 , OH, OCH 3 , SH, and SCH 3 ; and
wherein the compound of Formula (2b) includes pharmaceutically acceptable salts, solvates, enantiomers, and polymorphs of said compound of Formula (2b).
18 . The compound of claim 17 , wherein R 2 is ethyl.
19 . The compound according to claim 17 , wherein the compound of Formula (2b) is a single enantiomer.
20 . The compound of claim 17 , wherein the compound has the following formula:
wherein R 1 , R 2 , and X − are as defined in claim 17 .
21 . A method of treating anemia in a subject in need, the method comprising administering a therapeutically effective amount of an M4-specific antagonist to said subject.
22 . The method of claim 21 , wherein said M4-specific antagonist is a compound having the following formula:
wherein:
R 1 is H or CH 3 ;
R 2 is a hydrocarbon group having 1-3 carbon atoms;
R 3 , R 4 , and R 5 are independently selected from hydrogen atom, halogen atoms, CH 3 , CF 3 , OH, OCH 3 , SH, SCH 3 , and the following structure (1-1):
provided that one or two of R 3 , R 4 , and R 5 is the structure of Formula (1-1);
R 6 is H or CH 3 ;
R 7 , R 8 , and R 9 are independently selected from hydrogen atom, halogen atoms, CH 3 , CF 3 , OH, OCH 3 , SH, and SCH 3 ;
wherein the method results in increased self-renewal of BFU-E cells; and
wherein the compound of Formula (1) includes pharmaceutically acceptable salts, solvates, enantiomers, and polymorphs of said compound of Formula (1).
23 . The method of claim 21 , wherein said M 4 -specific antagonist is a compound having the following formula:
wherein:
R 2 is a hydrocarbon group having 1-3 carbon atoms; and
R 4 , R 5 , R 7 , R 8 , and R 9 are independently selected from hydrogen atom, halogen atoms, CH 3 , CF 3 , OH, OCH 3 , SH, and SCH 3 ;
wherein the method results in increased self-renewal of BFU-E cells; and
wherein the compound of Formula (2) includes pharmaceutically acceptable salts, solvates, enantiomers, and polymorphs of said compound of Formula (2).
24 . The method of claim 21 , wherein said M 4 -specific antagonist is a compound having the following formula:
R 1 is H or CH 3 ;
R 2 is a hydrocarbon group having 1-3 carbon atoms;
R 4 , R 5 , R 7 , R 8 , and R 9 are independently selected from hydrogen atom, halogen atoms, CH 3 , CF 3 , OH, OCH 3 , SH, and SCH 3 ;
wherein the method results in increased self-renewal of BFU-E cells; and
wherein the compound of Formula (2b) includes pharmaceutically acceptable salts, solvates, enantiomers, and polymorphs of said compound of Formula (2b).